Aneurismal subarachnoid hemorrhage is an increasing problem in the United States, affecting approximately 30,000 people every year. Despite advances in the neurosurgical field, approximately 50% of patients die within the first month after hemorrhage. In fact, most of them die even before reaching the hospital.
The management of cerebral aneurysms raises significant issues both at the diagnostic level and at the therapeutic level. For example, since no selection criteria exists and since their current diagnosis means are expensive and invasive (e.g., 4-axle digital subtraction angiography), no mass detection has yet been considered.
The rate of mortality and morbidity associated with treatment of aneurysms is also significant. For example, surgical clipping or endovascular coiling is responsible for 15% of the morbidity and mortality rate. Recurrence is not insignificant either with approximately 2.2% at 10 years and 9.0% at 20 years after successfully neck clipping.
Most of intracranial aneurysms are clinically quiescent until they rupture. The rate of rupture varies between 0.05% (International Study of Unruptured Intracranial Aneurysms) and 2.3% per year. After hemorrhage, the risk of rebleeding is about 40% for the first two months, then 3% per year after the sixth month. The devastating effects of aneurysm rupture advocates preventive treatment and/or diagnosis of unruptured aneurysms.
The most common cerebral aneurysm has the saccular form, a balloon-like distension of a major brain artery occurring at (or near) the apex of arterial forks. It is frequently (around 90%) located on the anterior part of the circle of Willis. Its prevalence varies from 1% to 8% on autopsy series.
Traditionally, craniotomy with aneurismal clipping has been employed to manage these patients, but endovascular embolization is moving to the forefront of treatment.
Surgical clipping of cerebral aneurysms involves the removal of a section of the skull, spreading of the brain tissue to reach the aneurysm and placement of a tiny metal clip across the neck of the aneurysm. Such procedure allows to stop blood flow into the aneurysm and to exclude it from the blood stream. After the aneurysm has been clipped, the bone is secured in its original place, and the wound is closed.
Endovascular therapy (e.g., endovascular coiling with Guglielmi detachable coil) is a minimally invasive procedure that accesses the treatment area from within the blood vessel. In the case of aneurysms, this treatment is called coil embolization, or “coiling”. In contrast to surgery, endovascular coiling does not require open surgery. Instead, physicians use real-time X-ray technology, called fluoroscopic imaging, to visualize the patient's vascular system and treat the disease from inside the blood vessel.
Endovascular treatment of brain aneurysms involves insertion of a catheter (small plastic tube) into the femoral artery in the patient's leg and navigating it through the vascular system, into the head and into the aneurysm. Tiny platinum coils are threaded through the catheter and deployed into the aneurysm, blocking blood flow into the aneurysm and preventing rupture. The coils are made of platinum so that they can be visible via X-ray and be flexible enough to conform to the aneurysm shape. This endovascular coiling, or filling of the aneurysm is called embolization and can be performed under general anesthesia or light sedation. More than 125,000 patients worldwide have been treated with detachable platinum coils.
The International Subarachnoid Aneurysm Trial (ISAT), a multi-center prospective randomized clinical trial has been performed for the purpose of comparing surgical clipping and endovascular coiling of ruptured aneurysm.
The study found that, in patients equally suited for both treatment options, endovascular coiling treatment was associated with substantially better patient outcomes than surgery in terms of survival free of disability at one year. The relative risk of death or significant disability at one year for patients treated with coils was 22.6 percent lower than in surgically-treated patients. However, the long-term follow-up will be essential to assess the durability of the substantial early advantage of endovascular coiling over conventional neurosurgical clipping for the treatment of brain aneurysms.
Although no multi-center randomized clinical trial comparing endovascular coiling and surgical treatment of unruptured aneurysms has yet been conducted for the treatment of unruptured aneurysm, retrospective analyses have found that endovascular coiling is associated with less risk of bad outcomes, shorter hospital stays and shorter recovery times than surgery.
In order to improve diagnosis and treatment, current research is performed to elucidate the pathogenesis of cerebral aneurism. A better understanding of the molecular mechanisms involved in the pathogenesis of cerebral aneurism will help to develop medical treatment.
Various hypotheses have been proposed regarding the developmental mechanisms of Saccular Cerebral Artery Aneurysms (SCAAs) such as the medial defect theory, the elastic lamellar theory, degenerative theory, congenital theories, and others. With the recent development of animal model of the disease, it has been possible to study early aneurismal changes and to elucidate the mechanisms of aneurysm formation and development. Studies have showed that hemodynamic stress induces the development of cerebral aneurysms causing degenerative changes of the endothelium, the elastic lamina and the medial smooth muscle cells at specific site on the arterial bifurcation. The anterior cerebral artery/olfactory artery (ACA/OA) junction is one of the favorite sites of aneurysm development. Its normal structure and changes due to aneurysm development have been widely studied. The apex of a normal ACA/OA junction consists of normal arterial components (endothelial cells, internal elastic lamina, medial smooth muscle cells, and thin adventitial fibrous connective tissue). In the apical region, there is an intimal protrusion called pad consistently located near the apex on the distal side of the ACA. This pad is composed of spindle-shaped cells similar to the medial smooth muscle cells, rich in interstitial tissue. Under and just distal to the intimal pad on the side of the ACA, the internal elastic lamina is thinned and fragmented. The initial changes of aneurysms are localized almost exclusively at the intimal pad and its neighboring distal portion. Internal elastic lamina shows various degenerative changes and disappearance. Different studies have reported severe changes in endothelium. Nagata et al. examined by scanning electron microscopy the luminal surface of the cerebral aneurysms. They noticed some variations in the shape of the endothelial cells from fusiform to polygonal. Some of them showed balloon-like protrusions. Crater-like depressions on the endothelial surface and small holes and enlarged gaps at the junction of the endothelial cells were frequently observed. Gap formation at the junctions between the endothelial cells was one of the most obvious changes on the luminal surface of the aneurysms. Kojima et al. studying various stages of early aneurismal changes reported alterations of the endothelium developing just distal to intimal pad. Degenerated cells with balloons and craters were observed intermingled with regenerated endothelial cells. Interendothelial gaps were also seen. They concluded that some hemodynamic stress, possibly turbulent flow or secondary flow may injure the endothelial cells located distal to the pad, and such injured endothelial cells in turn develop saccular cerebral aneurysms. Stehbens also described severe alterations of the endothelium and subendothelial tissues caused by hemodynamic stress. Kim et al. studied aneurismal changes in experimental monkeys and found endothelial injury. They suggested that aneurismal changes are initiated by degenerative changes in the endothelium, which are followed by alterations in the underlying elastic lamina and, in turn, in the medial layer.
Hazama et al. showed that early aneurismal changes consist in degenerative changes of the Internal Elastic Lamina (I.E.L) at the intimal pad and the neighboring area distal to the pad associated to regressive changes of medial smooth muscle layer. Kim et al. also reported degenerative changes of the I.E.L and medial smooth muscle layer. Morimoto et al. found that the characteristic of SCAA formation in a mouse model was thinning of medial smooth muscle layer and disappearance of the I.E.L. Kondo et al. found that the histological features of aneurismal changes were thinning of the medial layer accompanied by fragmentation or disappearance of internal elastic lamina with wall dilatation. They noted a decreased number of SMCs in the medial layer due to apoptosis. They concluded that the death of medial SMCs through apoptosis plays an important role in aneurysm formation. Frosen et al. found different histological types of saccular cerebral artery aneurysms (SCAAs). Lack of elastic laminas was a common feature in the SCAAs studied. Type A was characterized by endothelialized wall with linearly organized SMC, type B by thickened wall with disorganized SMC, type C by hypocellular wall with either myo-intimal proliferation or thrombosis, type D by an extremely thin thrombosis-lined hypocellular wall.
The precise molecular mechanisms involved in the pathogenesis of cerebral aneurysms have not yet been conclusively identified. Hemodynamic stress has been shown in many investigations to be the major cause of various degenerative changes in SCAA formation. This hemodynamic stress might induce a complex, multifactorial remodeling through a variety of mediators and pathways. Recent studies have reported the role of nitric oxide in the development of SCAA. Inducible NO synthase (iNOS) was induced in response to hemodynamic stress and NO synthesized by iNOS serves to damage the arterial wall and lead to aneurysm formation. Other molecular mechanisms such as active expressions of matrix metalloproteinases, apoptosis of medial smooth muscle cells have been shown associated with SCAA. The role of elastase in the degradation of I.E.L in early aneurismal lesions has also been discussed. Nagata et al. reported that in experimental aneurysms many leukocytes were present adhering to the inter endothelial gaps, which may represent the participation of leukocytes in degradation of the I.E.L. Cajander and Hassler also found extracellular lysosome-like granules closely connected to the disintegrated elastic lamella in the mouths of aneurysms and hypothesized that discharged leukocyte granules containing elastase help to destroy the elastic lamella. Enhanced activity of elastase in the arterial wall may also participate in the degenerative changes of the internal elastic lamina, as in the case of hypertension
It is an object of the present invention to provide a method for non-invasive diagnosis and treatment of intra-cranial aneurysms